4″-deoxy-4″-(S)-amido avermectin derivatives

ABSTRACT

A compound of formula (I); that has the S-configuration at the 4″-position and wherein the bond between carbon atoms 22 and 23 is a single or a double bond; R 1  is C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl; or C 2 -C 12 alkenyl; R 2  is H, or, for example, unsubstituted or mono- to penta-substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or C 1 -C 6 alkoxy-C 1 -C 6 alkyl; R 3  is H or, for example, C 1 -C 12 alkyl; X is a bond, O, NR 4  or S; and Z is C═O, C═S or S0 2 ; and, where applicable, E/Z isomers, mixtures of E/Z isomers and/or tautomers, in each case in free form or in salt form; a process for the preparation of and the use of those compounds and their isomers and tautomers; starting materials for the preparation of the compounds of formula (I); pesticidal compositions in which the active ingredient has been selected from those compounds and their tautomers; and a method of controlling pests using those compositions are described.

This application is a 371 of International Application No.PCT/EP03/04740 filed May 6, 2003, which claims priority to CH 774/02,filed May 7, 2002, the contents of which are incorporated herein byreference.

The invention relates to (1) a compound of formula

that has the S-configuration at the 4″-position and wherein

the bond between carbon atoms 22 and 23 is a single or a double bond;

R₁ is C₁-C₁₂alkyl, C₃-C₈acycloalkyl; or C₂-C₁₂alkenyl;

R₂ is H, C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₁-C₆alkoxy-C₁-C₆alkyl, C₃-C₈cycloalkyl, —C(═O)—R₅, aryl or heteroaryl;wherein the C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl,C₁-C₆alkoxy-C₁-C₆alkyl, C₃-C₈cycloalkyl, aryl and heteroarylsubstituents may be unsubstituted or mono- to penta-substituted;

R₃ is H, C₁-C₁₂alkyl, C₃-C₁₂cycloalkyl, C₂-C₁₂alkenyl or C₂-C₁₂alkynyl;wherein the C₁-C₁₂alkyl, C₃-C₁₂cycloalkyl, C₂-C₁₂alkenyl andC₂-C₁₂alkynyl substituents may be unsubstituted or mono- topenta-substituted;

X is a bond, O, NR₄ or S;

Z is C═O, C═S or SO₂;

R₄ is H, C₁-C₈alkyl, C₃-C₈cycloalkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, benzylor —C(═O)—R₅; or

R₂ and R₄ together are a three- to seven membered alkylene or alkenylenebridge,

wherein the alkylene or alkenylene bridges are unsubstituted or mono totri-substituted; and

wherein one of the methylene groups of the three- to seven memberedalkylene- or alkenylene-bridge may be replaced by O, NH, S, S(═O) orSO₂; and

wherein the substituents of the mentioned alkyl, alkenyl, alkynyl,cycloalkyl, alkylene, alkenylene, aryl and heteroaryl radicals asdefined under R₂, R₃ and R₄ are selected from the group consisting ofOH, ═O, halogen, halo-C₁-C₂alkyl, CN, NO₂, —N₃, C₃-C₈cycloalkyl that isunsubstituted or substituted by from one to three methyl groups;norbornylenyl; C₃-C₈cycloalkenyl that is unsubstituted or substituted byfrom one to three methyl groups; C₃-C₈halo-cycloalkyl, C₁-C₁₂alkoxy,C₁-C₆alkoxy-C₁-C₆alkyl, C₃-C₈cycloalkoxy, C₁-C₁₂haloalkoxy,C₁-C₁₂alkylthio, C₃-C₈cycloalkylthio, C₁-C₁₂haloalkylthio,C₁-C₁₂alkylsulfinyl, C₃-C₈cycloalkylsulfinyl, C₁-C₁₂haloalkylsulfinyl,C₃-C₈halocycloalkylsulfinyl, C₁-C₁₂alkylsulfonyl,C₃-C₈cycloalkylsulfonyl, C₁-C₁₂haloalkylsulfonyl,C₃-C₈halocycloalkylsulfonyl, C₂-C₈alkenyl, C₂-C₈alkynyl, NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, —C(═O)R₅, —NHC(═O)R₆, ═NO—C₁-C₆alkyl,—P(═O)(OC₁-C₆alkyl)₂; aryl, heterocyclyl, aryloxy, heterocyclyloxy; andaryl, heterocyclyl, aryloxy and heterocyclyloxy that, depending upon thepossibilities of substitution at the ring, are mono- topenta-substituted by substituents selected from the group consisting ofOH, ═O, halogen, CN, NO₂, —N₃, C₁-C₁₂alkyl, C₃-C₈cycloalkyl,C₁-C₁₂haloalkyl, C₁-C₁₂alkoxy, C₁-C₁₂haloalkoxy, C₁-C₁₂alkylthio,C₁-C₁₂haloalkylthio, C₁-C₆alkoxy-C₁-C₆alkyl, dimethyl-amino-C₁-C₆alkoxy,C₂-C₈alkenyl, C₂-C₈alkynyl, phenoxy and phenyl-C₁-C₆alkyl; phenoxy thatis unsubstituted or substituted by from one to three substituentsselected independently of one another from halogen, methoxy,trifluoromethyl and trifluoromethoxy; phenyl-C₁-C₆alkoxy that isunsubstituted or substituted in the aromatic ring by from one to threesubstituents selected independently of one another from halogen,methoxy, trifluoromethyl and trifluoromethoxy; phenyl-C₂-C₆alkenyl,phenyl-C₂-C₆alkynyl, methylenedioxy, —C(═O)R₅, —O—C(═O)R₆, —NH—C(═O)R₆,NH₂, NH(C₁-C₁₂alkyl), N(C₁-C₁₂alkyl)₂, C₁-C₆alkylsulfinyl,C₃-C₈cycloalkylsulfinyl, C₁-C₆haloalkylsulfinyl,C₃-C₈halocycloalkylsulfinyl, C₁-C₆alkylsulfonyl,C₃-C₈cycloalkylsulfonyl, C₁-C₆haloalkylsulfonyl andC₃-C₈halocycloalkylsulfonyl;

R₅ is H, OH, SH, NH₂, NH(C₁-C₁₂alkyl), N(C₁-C₁₂alkyl)₂, C₁-C₁₂alkyl,C₃-C₈cycloalkyl C₁-C₁₂haloalkyl, C₁-C₁₂alkoxy, C₁-C₁₂haloalkoxy,C₁-C₆alkoxy-C₁-C₆alkoxy, C₁-C₁₂alkylthio, C₂-C₈alkenyloxy,C₂-C₈alkynyloxy; phenyl, phenoxy, benzyloxy, NH-phenyl,—N(C₁-C₆alkyl)-phenyl, NH—C₁-C₆alkyl-C(═O)—R₇,—N(C₁-C₆alkyl)-C₁-C₆alkyl-C(═O)—R₇; or phenyl, phenoxy, benzyloxy,NH-phenyl or —N(C₁-C₆alkyl)-phenyl each of which is substituted in thearomatic ring by from one to three substituents selected independentlyof one another from halogen, C₁-C₆alkoxy, C₁-C₆haloalkyl andC₁-C₆haloalkoxy;

R₆ is H, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl, C₂-C₈alkenyl, C₂-C₈alkynyl,phenyl, benzyl, NH₂, NH(C₁-C₁₂alkyl), N(C₁-C₁₂alkyl)₂, —NH-phenyl or—N(C₁-C₁₂alkyl)-phenyl; and

R₇ is H, OH, C₁-C₁₂alkyl, C₁-C₁₂alkoxy, C₁-C₆alkoxy-C₁-C₆alkoxy,C₂-C₈alkenyloxy, phenyl, phenoxy, benzyloxy, NH₂, NH(C₁-C₁₂alkyl),N(C₁-C₁₂alkyl)₂, —NH-phenyl or —N(C₁-C₁₂alkyl)-phenyl;

and, where applicable, to E/Z isomers, mixtures of E/Z isomers and/ortautomers, in each case in free form or in salt form;

with the proviso that Z is not C═O when X is a bond, R₂ is CH₃ or2-aminoethyl, R₃ is hydrogen, the bond between carbon atoms 22 and 23 isa double bond and R₁ is i-propyl or sec-butyl;

to a process for the preparation of and to the use of those compoundsand their isomers and tautomers; to starting materials for thepreparation of the compounds of formula (I); to pesticidal compositionsin which the active ingredient has been selected from the compounds offormula (I) and their tautomers; and to a method of controlling pestsusing those compositions.

Certain macrolide compounds are proposed for pest control in theliterature. The biological properties of those known compounds are notentirely satisfactory, however, for which reason there is a need toprovide further compounds having pesticidal properties, especially forthe control of insects and members of the order Acarina. That problem issolved according to the invention by the provision of the presentcompounds of formula (I) wherein, at the 4″-position, theS-configuration is present.

The compounds claimed according to the invention are derivatives ofavermectin. Avermectins are known to the person skilled in the art. Theyare a group of structurally closely related pesticidally activecompounds which are obtained by fermentation of astrain of themicroorganism Streptomyces avermitilis. Derivatives of avermectins canbe obtained via conventional chemical syntheses.

The avermectins obtainable from Streptomyces avermitilis are designatedA1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b. Compounds with thedesignation “A” have a methoxy radical in the 5-position; thosecompounds designated “B” have an OH group. The “a” series comprisescompounds wherein the substituent R₁ (in position 25) is a sec-butylradical; in the “b” series there is an isopropyl radical in the25-position. The number 1 in the name of a compound indicates that atoms22 and 23 are bonded by a double bond; the number 2 indicates that theyare bonded by a single bond and carbon atom 23 carries an OH group. Theabove designations are retained in the description of the presentinvention in order in the case of the non-natural avermectin derivativesaccording to the invention to indicate the specific structural typecorresponding to natural avermectin. There are claimed according to theinvention derivatives of compounds of the B1 series and relatedcompounds having a single bond between carbon atoms 22 and 23 as well ascompounds having other substituents such as cyclohexyl or 1-methylbutylin the position R₁, more especially mixtures of derivatives ofavermectin B₁a and B₁b in which, at the 4″-position, the S configurationis present.

Some of the compounds of formula (I) may be in the form of tautomers.Accordingly, any reference to the compounds of formula (I) hereinbeforeand hereinafter is to be understood, where applicable, as including alsocorresponding tautomers, even if the latter are not specificallymentioned in every case.

The compounds of formula (I) and, where applicable, their tautomers canform salts, for example acid addition salts. These acid addition saltsare formed, for example, with strong inorganic acids, such as mineralacids, for example sulfuric acid, a phosphoric acid or a hydrohalicacid, with strong organic carboxylic acids, such as unsubstituted orsubstituted, for example halo-substituted, C₁-C₄alkanecarboxylic acids,unsaturated or saturated dicarboxylic acids, or hydroxycarboxylic acids;or with organic sulfonic acids, such as unsubstituted or substituted,for example halo-substituted, C₁-C₄alkane- or aryl-sulfonic acids.Compounds of formula (I) that have at least one acidic group canfurthermore form salts with bases. Suitable salts with bases are, forexample, metal salts, such as alkali metal salts or alkaline earth metalsalts, for example sodium, potassium or magnesium salts, or salts withammonia or with an organic amine, such as morpholine, piperidine,pyrrolidine, a mono-, di- or tri-lower alkylamine, for exampleethylamine, diethylamine, triethylamine or dimethylpropylamine, or amono-, di- or tri-hydroxy-lower alkylamine, for example mono-, di- ortriethanolamine. Corresponding internal salts may also be formed whereappropriate. The free form is preferred. Among the salts of thecompounds of formula (I), the agrochemically advantageous salts arepreferred. Hereinbefore and hereinafter, any reference to the freecompounds of formula (I) or their salts is to be understood asincluding, where appropriate, also the corresponding salts or the freecompounds of formula (I), respectively. The same applies to tautomers ofcompounds of formula (I) and salts thereof.

Preferred anions of salts of compounds of formula (I) are: the anion ofa mineral acid, such as, for example, sulfuric acid, a phosphoric acidor a hydrohalic acid;

the anion of an organic carboxylic acid, such as an unsubstituted orsubstituted, for example halo-substituted, C₁-C₄alkanecarboxylic acid,an unsaturated or saturated dicarboxylic acid, or a hydroxycarboxylicacid;

the anion of an organic sulfonic acid, such as an unsubstituted orsubstituted, for example halo-substituted, C₁-C₄alkane- or aryl-sulfonicacid; or

the anion of a C—H-active compound. These C—H-active compounds includeespecially organic compounds carrying strongly electron-attractingsubstituents, such as nitriles, carbonyls or nitro groups. Preference isgiven especially to anions of compounds of the formula Y₁—CH₂—Y₂,wherein Y₁ and Y₂ each represents an electron-attracting group.Preference is given more especially to the anions of malodinitrile,cyanoacetic acid, esters of cyanoacetic acid, amides of cyanoaceticacid, acetoacetic acid, esters of acetoacetic acid, acetyl acetone,cyanoacetone and barbituric acid; or

the anion of an acid phenol, such as, for example, picric acid.

Preference is given most especially to 1:1 salts of compounds of formula(I) with the following acids: benzoic acid, maleic acid, fumaric acid,2-hydroxybenzoic acid, salicylic acid, malic acid, benzenesulfonic acid,barbituric acid, 2-ethylbutyric acid, thiomalic acid,3,5-dihydroxy-benzoic acid, trimesic acid, D-(−)-quinic acid,2-bromo-benzoic acid, 2-phenyl-benzoic acid, 3,3′-thiodipropionic acid,naphthalene-1-carboxylic acid, 5-sulfosalicylic acid,2-methoxy-phenylacetic acid, benzene-1,2,4-tricarboxylic acid,3-hydroxy-benzoic acid, D-gluconic acid, 4,5-dichloro-phthalic acid,n-hexanoic acid (caproic acid), n-heptanoic acid (oenanthic acid),n-octanoic acid (caprylic acid), stearic acid, palmitic acid,2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-4,4′-methylene-bis(3-hydroxy-2-naphthoicacid), embonic acid, 4-methoxy-phenylacetic acid (homoanisic acid),2-anisic acid (2-methoxy-benzoic acid), adamantane-1-carboxylic acid,pyridine-3,4-dicarboxylic acid, 3,4-dihydroxy-benzoic acid,1-hydroxy-2-naphthoic acid (1-naphthol-2-carboxylic acid),2,2′-oxydiacetic acid (diglycolic acid), O-ethyl-glycolic acid,(2-naphthylthio)-acetic acid (S-(2-naphthyl)-thioglycolic acid),2-naphthyloxy-acetic acid, perfluoro-octanoic acid, p-toluic acid,cyclohexanepropionic acid, 2,6-dihydroxypyridine-4-carboxylic acid(citrazinic acid), 3-methoxypropionic acid, 3,4,5-trihydroxy-benzoicacid (gallic acid), pyromucic acid (furan-2-carboxylic acid),2-methyl-benzoic acid (o-toluic acid), 3,6,9-trioxa-undecanedioic acid,3-(4-methoxyphenyl)-propionic acid (p-methoxy-hydrocinnamic acid),3-(3,4-dihydroxyphenyl)-propionic acid, O-acetyl-salicylic acid(aspirin), 3-fluoro-benzoic acid, cyclohexanecarboxylic acid,5-chloro-2-hydroxy-benzoic acid (5-chloro-salicylic acid),2,5-dimethyl-benzoic acid (p-xylic acid), 3,4,5-trimethoxy-benzoic acid(trimethylgallic acid), 2,4,6-trimethyl-benzoic acid, 3-phenoxy-benzoicacid, 4-phenyl-butyric acid, 3-trifluoromethyl-benzoic acid,terephthalic acid monomethyl ester, o-hydroxy-phenyl-acetic acid,isophthalic acid, 2,4,6-trihydroxy-benzoic acid,trifluoromethanesulfonic acid, 2-methyl-propionic acid (iso-butyricacid), 2,4-dimethoxy-benzoic acid, 2-thienylacetic acid(thiophene-2-acetic acid), 3,4-dimethoxy-benzoic acid (veratric acid),2,2-bis(hydroxy-methyl)-propionic acid , 2-fluoro-phenylacetic acid,2-methyl-butyric acid, hydroxy-acetic acid, 4-chloro-phenylacetic acid,2-mercaptobenzoic acid (thiosalicylic acid),(+/−)-2-hydroxyphenyl-acetic acid (DL-mandelic acid),2,4-dihydroxypyrimidine-6-carboxylic acid, toluene-4-sulfonic acid(p-toluene-sulfonic acid), 2-chloro-phenylacetic acid,2,4-dichloro-benzoic acid, 2,6-dichloro-benzoic acid,2-mercapto-propionic acid (thiolactic acid), 2-chloro-benzoic acid,methanesulfonic acid, ethanesulfonic acid (ethyl-sulfuric acid),4-phenoxy-butyric acid, 4-tert-butyl-benzoic acid,3,4-methylenedioxy-benzoic acid, bis(2-carboxyethyl)-disulfide, pivalicacid (trimethylacetic acid), nicotinic acid N-oxide, acrylic acid,3-benzoyl-propionic acid (4-oxo-4-phenyl-butyric acid),(1R)-(−)-camphor-10-sulfonic acid hydrate, 2-chloro-4-fluoro-benzoicacid, 3,5-dimethoxy-benzoic acid, 2-sulfobenzoic acid, sulfoacetic acid,2-chloro-6-fluoro-benzoic acid, 2,4-dihydroxy-benzoic acid,methoxyacetic acid, 2,4,6-trimethyl-benzene-sulfonic acid, tartaricacid, xanthene-9-carboxylic acid, 4-pentenoic acid (allylacetic acid),5-sulfosalicylic acid, vinylacetic acid, 2-butynedioic acid(acetylenedicarboxylic acid), 2-oxo-propionic acid (pyruvic acid),cyclohexylacetic acid, 2-hydroxyisobutyric acid, nicotinic acid,6-chloro-nicotinic acid, isonicotinic acid, picolinic acid,pyrazinecarboxylic acid, oxalic acid, propionic acid,pentafluoropropionic acid, butyric acid, heptafluorobutyric acid,valeric acid, citric acid, glyceric acid, acetic acid, chloroaceticacid, dichloroacetic acid, trifluoroacetic acid, fluoroacetic acid,lactic acid, malonic acid, succinic acid, glutaric acid, adipic acid,pimelic acid, suberic acid, azelaic acid, sebacicacid, phthalic acid,terephthalic acid, phosphoric acid, sulfuric acid, hydrochloric acid,hydrobromic acid, hydriodic acid, nitric acid, perchloric acid,acetoacetic acid, cyanoacetic acid, tetrahydrofuran-2-carboxylic acid,propiolic acid, methacrylic acid, crotonic acid and picric acid.

Unless defined otherwise, the general terms used hereinbefore andhereinafter have the meanings given below.

Unless defined otherwise, carbon-containing groups and compounds eachcontain from 1 up to and including 6, preferably from 1 up to andincluding 4, especially 1 or 2, carbon atoms.

Halogen—as a group per se and as a structural element of other groupsand compounds, such as haloalkyl, haloalkoxy and haloalkylthio—isfluorine, chlorine, bromine or iodine, especially fluorine, chlorine orbromine, more especially fluorine or chlorine.

Alkyl—as a group per se and as a structural element of other groups andcompounds, such as haloalkyl, alkoxy and alkylthio—is, in each casegiving consideration to the number of carbon atoms contained in thegroup or compound in question, either straight-chained, i.e. methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl, or branched, e.g.isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl orisohexyl.

Cycloalkyl—as a group per se and as a structural element of other groupsand compounds, such as halocycloalkyl, cycloalkoxy andcycloalkylthio—is, in each case giving due consideration to the numberof carbon atoms contained in the group or compound in question,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl.

Alkenyl—as a group per se and as a structural element of other groupsand compounds—is, giving due consideration to the number of carbon atomsand conjugated or isolated double bonds contained in the group inquestion, either straight-chained, e.g. vinyl, allyl, 2-butenyl,3-pentenyl, 1-hexenyl, 1-heptenyl, 1,3-hexadienyl or 1,3-octadienyl, orbranched, e.g. isopropenyl, isobutenyl, ispprenyl, tert-pentenyl,isohexenyl, isoheptenyl or isooctenyl. Alkenyl groups having from 3 to12, especially from 3 to 6, more especially 3 or 4, carbon atoms arepreferred.

Alkynyl—as a group per se and as a structural element of other groupsand compounds—is, in each case giving due consideration to the number ofcarbon atoms and conjugated or isolated double bonds contained in thegroup or compound in question, either straight-chained, e.g. ethynyl,propargyl, 2-butynyl, 3-pentynyl, 1-hexynyl, 1-heptynyl, 3-hexen-1-ynylor 1,5-heptadien-3-ynyl, or branched, e.g. 3-methylbut-1-ynyl,4-ethylpent-1-ynyl, 4-methylhex-2-ynyl or 2-methylhept-3-ynyl. Alkynylgroups having from 3 to 12, especially from 3 to 6, more especially 3 or4, carbon atoms are preferred.

Alkylene and alkenylene are straight-chain or branched bridge members;they are in particular —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—,—CH₂(CH₃)CH₂CH₂—, —CH₂C(CH₃)₂CH₂—, —CH₂CH═CH—, —CH₂CH═CHCH₂ or—CH₂CH═CHCH₂CH₂—.

Halo-substituted carbon-containing groups and compounds, such as alkyl,alkenyl, alkynyl, cycloalkyl, alkoxy or alkylthio substituted byhalogen, may be partially halogenated or perhalogenated, it beingpossible in the case of polyhalogenation for the halogen substituents tobe the same or different. Examples of haloalkyl—as a group per se and asa structural element of other groups and compounds, such as haloalkoxyand haloalkylthio—are methyl substituted from one to three times byfluorine, chlorine and/or bromine, such as CHF₂ or CF₃; ethylsubstituted from one to five times by fluorine, chlorine and/or bromine,such as CH₂CF₃, CF₂CF₃, CF₂CCl₃, CF₂CHCl₂, CF₂CHF₂, CF₂CFCl₂, CF₂CHBr₂,CF₂CHClF, CF₂CHBrF or CClFCHClF; propyl or isopropyl substituted fromone to seven times by fluorine, chlorine and/or bromine, such asCH₂CHBrCH₂Br, CF₂CHFCF₃, CH₂CF₂CF₃ or CH(CF₃)₂; butyl or an isomerthereof substituted from one to nine times by fluorine, chorine and/orbromine, such as CF(CF₃)CHFCF₃ or CH₂(CF₂)₂CF₃; pentyl or an isomerthereof substituted from one to eleven times by fluorine, chlorineand/or bromine, such as CF(CF₃)(CHF)₂CF₃ or CH₂(CF₂)₃CF₃; and hexyl oran isomer thereof substituted from one to thirteen times by fluorine,chlorine and/or bromine, such as (CH₂)₄CHBrCH₂Br, CF₂(CHF)₄CF₃,CH₂(CF₂)₄CF₃ or C(CF₃)₂(CHF)₂CF₃.

Aryl is especially phenyl, naphthyl, anthracenyl or perylenyl,preferably phenyl.

Heterocyclyl is especially pyridyl, pyrimidyl, s-triazinyl,1,2,4-triazinyl, thienyl, furyl, tetrahydrofuranyl, pyranyl,tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,triazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl,quinolinyl, quinoxalinyl, benzofuranyl, benzimidazolyl, benzopyrrolyl,benzothiazolyl, indolyl, coumarinyl or indazolyl, which are preferablybonded via a carbon atom; preference is given to thienyl, thiazolyl,benzofuranyl, benzothiazolyl, furyl, tetrahydropyranyl and indolyl;especially pyridyl or thiazolyl.

Within the scope of the present invention, preference is given to

(2) compounds according to group (1) of formula (I) wherein R₁ isisopropyl or sec-butyl, preferably wherein a mixture of the isopropyland the sec-butyl derivative is present;

(3) compounds according to group (1) or (2) of formula (I) wherein R₂ isH;

(4) compounds according to group (1) or (2) of formula (I) wherein R₂ isunsubstituted or substituted, especially unsubstituted, C₁-C₈alkyl, mostespecially methyl;

(5) compounds according to group (1) or (2) of formula (I) wherein R₂ isethyl;

(6) compounds according to group (1) or (2) of formula (I) wherein R₂ isn-propyl;

(7) compounds according to any one of groups (1) to (6) of formula (I)wherein R₃ is unsubstituted or substituted, especially unsubstituted,C₁-C₁₂alkyl;

(8) compounds according to any one of groups (1) to (6) of formula (I)wherein R₃ is hydrogen;

(9) compounds according to any one of groups (1) to (7) of formula (I)wherein R₃ is methyl;

(10) compounds according to any one of groups (1) to (7) of formula (I)wherein R₃ is ethyl;

(11) compounds according to any one of groups (1) to (7) of formula (I)wherein R₃ is n-propyl;

(12) compounds according to any one of groups (1) to (7) of formula (I)wherein R₃ is iso-propyl;

(13) compounds according to any one of groups (1 ) to (7) of formula (I)wherein R₃ is n-butyl, sec-butyl, iso-butyl or tert-butyl;

(14) compounds according to any one of groups (1), (2), (4) and (7) to(13) of formula (I) wherein R₂ is substituted C₁-C₄alkyl and thesubstituents are selected from the group consisting of OH, halogen,C₃-C₈cycloalkyl; C₃-C₈cycloalkenyl that is unsubstituted or substitutedby from one to three methyl groups; C₁-C₁₂alkoxy, C₂-Calkenyl,C₂-C₈alkynyl, —C(═O)—R₅, —NHC(═O)R₆, —P(═O)(OC₁-C₆alkyl)₂; and phenyl,naphthyl, anthracenyl, phenanthrenyl, fluorenyl, perylenyl andheterocyclyl which are unsubstituted or, depending upon thepossibilities of substitution at the ring, mono- to penta-substituted;

especially wherein the substituents of R₂ are selected from the groupconsisting of halogen, C₃-C₈cycloalkyl, C₂-C₈alkynyl, —C(═O)—R₅,—NHC(═O)R₆, —P(═O)(OC₁-C₆alkyl)₂; and phenyl, naphthyl, anthracenyl,pyridyl, thiazolyl, imidazolyl, furyl, quinolinyl and pyrazolyl whichare unsubstituted or, depending upon the possibilities of substitutionat the ring, mono- to tri-substituted;

(15) compounds according to any one of groups (1), (2) and (7) to (14)of formula (I) wherein R₂ is unsubstituted or substituted, especiallyunsubstituted, C₁-C₆alkoxy-C₁-C₆alkyl;

(16) compounds according to any one of groups (1) to (6), (14) and (15)of formula (I) wherein R₃ is benzyl that carries on the aromatic moietyfrom one to three substituents that are selected from the groupconsisting of OH, halogen, CN, NO₂, C₁-C₂alkyl,dimethylamino-C₁-C₄alkoxy, C₃-C₆cycloalkyl, C₁-C₂haloalkyl, C₁-C₂alkoxy,C₁-C₂haloalkoxy, phenoxy, phenyl-C₁-C₆alkyl, phenyl-C₁-C₄alkenyl;phenoxy that is unsubstituted or substituted by chlorine or methoxy;benzyloxy that is unsubstituted or substituted by chlorine, methoxy ortrifluoromethyl; methylenedioxy, —C(═O)—R₅, —O—C(═O)R₆ and NHC(═O)R₆;

R₅ is H, OH, NH₂, NH(C₁-C₂alkyl), N(C₁-C₂alkyl)₂,—O—C₁-C₂alkyl-C(═O)—R₇, NHC₁-C₂alkyl-C(═O)—R₇, C₁-C₆alkyl, C₁-C₂alkoxy,C₁-C₂alkoxy-C₁-C₂alkoxy, C₂-C₄alkenyloxy, C₂-C₄alkynyloxy; phenyl,phenoxy, benzyloxy, NH-phenyl, NH—C₁-C₆alkyl-C(═O)—R₇; or phenyl,phenoxy, benzyloxy, NH-phenyl that are substituted by halogen, nitro,methoxy, trifluoromethyl or trifluoromethoxy;

R₆ is H, C₁-C₃alkyl, phenyl or benzyl; and

R₇ is H, OH, NH₂, NH(C₁-C₁₂alkyl), N(C₁-C₁₂alkyl)₂, C₁-C₁₂alkyl,C₁-C₁₂alkoxy, C₁-C₆alkoxy-C₁-C₆alkoxy, C₂-C₈alkenyloxy, phenyl, phenoxy,benzyloxy or NH-phenyl;

(17) compounds according to any one of groups (1), (2) and (7) to (13)of formula (I) wherein R₂ is C₁-C₄alkyl-C(═O)—R₅, especially—CH₂—C(═O)—R₅; and

R₅ is H, OH, NH₂, NH(C₁-C₂alkyl), N(C₁-C₂alkyl)₂, C₁-C₄alkyl,C₁-C₁₂alkoxy, C₂-C₄-alkenyloxy, phenyl, phenoxy, benzyloxy, NH-phenyl,NH—C₁-C₂alkyl-C(═O)—O—C₁-C₂alkyl-phenyl, —P(═O)(OC₁-C₆alkyl)₂; orphenyl, phenoxy, benzyloxy or NH-phenyl that are substituted bychlorine, fluorine, methoxy, trifluoromethyl or trifluoromethoxy;

most especially wherein R₅ is C₁-C₁₂alkoxy;

(18) compounds according to any one of groups (1), (2) and (7) to (13)of formula (I) wherein R₂ is —CH₂-heterocyclyl and heterocyclyl ispyridyl, furyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl,pyrazolyl, imidazolyl, thiazolyl, benzothienyl, quinolinyl,quinoxalinyl, benzofuranyl, benzimidazolyl, benzopyrrolyl,benzothiazolyl, indolyl, coumarinyl or indazolyl, the mentioned radicalsbeing unsubstituted or mono- or di-substituted by substituents selectedindependently of one another from halogen, trifluoromethyl,trifluoromethoxy and nitro; especially preferably pyridyl, furyl,pyrazolyl, imidazolyl, thiazolyl, benzimidazolyl, benzopyrrolyl,benzothiazolyl or indolyl each of which is unsubstituted or mono- ordi-substituted by substituents selected independently of one anotherfrom halogen, trifluoromethyl, trifluoromethoxy and nitro; especiallypyridyl or thiazolyl each of which is unsubstituted or mono- ordi-substituted by substituents selected independently of one anotherfrom halogen, trifluoromethyl, trifluoromethoxy and nitro, especiallymono-substituted by chlorine;

(19) compounds according to any one of groups (1) to (6) of formula (I)wherein R₃ is C₂-C₁₀alkenyl, especially C₂-C₄alkenyl, that isunsubstituted or mono- or di-substituted, especially mono-substituted,by C₂-C₄alkynyl, —C(═O—C₁-C₄alkoxy, —C(═O)—O-benzyl, phenyl or byhalogen; especially wherein R₃ is —CH₂—CH═CH₂;

(20) compounds according to any one of groups (1) to (19) of formula (I)wherein Z is —C(═O);

(21) compounds according to any one of groups (1 ) to (19) of formula(I) wherein Z is —C(═S);

(22) compounds according to any one of groups (1) to (21) of formula (I)wherein X is a bond;

(23) compounds according to any one of groups (1) to (21) of formula (I)wherein X is O;

(24) compounds according to any one of groups (1) to (21) of formula (I)wherein X is NR₄ especially NH;

(25) compounds according to any one of groups (1) to (21) of formula (I)wherein X is S;

(26) compounds according to any one of groups (1) to (25) of formula (I)wherein the bond between carbon atoms 22 and 23 is a single bond;

(27) compounds according to any one of groups (1) to (25) of formula (I)wherein the bond between carbon atoms 22 and 23 is double bond;

(28) compounds according to any one of groups (1) or (3) to (27) of theformula (I) in which R, is cyclohexyl;

(29) compounds according to any one of groups (1) or (3) to (27) of theformula (I) in which R₁ is 1-methyl-butyl;

(30) compounds according to any one of groups (1), (2) and (26) to (29)of the formula (I) in which R₂ is C₁-C₆alkoxy-C₁-C₆alkyl.

(31) compounds according to any one of groups (1), (2) and (26) to (29)of the formula (I) in which the group R₂—X-Z is —C(═O)H.

(32) compounds according to any one of groups (1), (2) and (26) to (29)of the formula (I) in which group —NR₃-Z-X—R₂ is —N(CH₃)C(═O)CH₃;

(33) special preference is given within the scope of the invention tothe compounds of formula (I) listed in the Tables, and, whereapplicable, their E/Z isomers and mixtures of E/Z isomers.

The intermediates of the following formulae

which are used for the preparation of the compounds of formula (I) andwherein R₃ is as defined above for formula (I), and A₁ and A₂ are groupsof the formula

respectively, wherein Sa is a protecting group and R₁ is as definedabove for formula (I) and the bond between carbon atoms 22 and 23 is asingle or a double bond, and wherein the said elements A1 and A2 orconnected to the remainder of the structure via carbon atom 13, can beobtained, for example, by

(A) reacting a compound of formula

wherein A₂ is as defined above for formula (II) and which is known orcan be prepared by methods known per se, with a sulfonic acid derivativeto form a compound of formula

wherein Q is a sulfonic acid radical and A₂ is as defined above forformula (IIb);

(B) reacting the resulting compound of formula (III) with an azide salt,with inversion at the 4″-position, to form a compound of formula

wherein the radical A₂ is as defined above; or, where appropriate,

(C) for the preparation of a compound of formula (IVb), reacting acompound of formula (IIIb) with an azide in the presence oftriphenylphosphine or a trialkylphosphine and an azodicarboxylic acidderivative;

(D) removing the protecting group Sa of the compound of formula (IVb) byreaction with an acid to form a compound of formula

wherein A₁ is as defined above;

(E) for the preparation of a compound of formula

wherein R₃ is —CH₂—R₃₃ and R₃₃ is unsubstituted or mono- topenta-substituted C₁-C₁₁alkyl, unsubstituted or mono- topenta-substituted C₂-C₁₁alkenyl, or unsubstituted or mono- topenta-substituted C₂-C₁₁lalkynyl, and A₂ corresponds to the macrocyclicstructure defined for formula (II), reacting a compound of formula (IVb)first

(E1) with a phosphine or a phosphite; then

(E2) with an aldehyde of the formula R₃₃—CHO; and then

(E3) with a hydride, where appropriate in the presence of a catalyticamount of acid;

(F) removing the protecting group from the resulting compound of formula(IIb) analogously to process step (D); or

(G) for the preparation of a compound of formula (IIa) wherein R₃ is asdefined in process step (E), reacting a compound of formula (IVa)analogously to process steps (E1) to (E3);

(H) for the preparation of a compound of formula (II) wherein R₃ is—CH₃, reacting a compound of formula (IV) first

(H1) with a phosphine; then

(H2) with formaldehyde, preferrably in the presence of a molecularsieve; and then

(H3) with a hydride in the presence of a catalytic amount of acid; andfurther reacting the resulting compound of formula

wherein A₂ corresponds to the macrocyclic structure defined for formula(II), analogously to process step (D); or

(I) for the preparation of a compound of formula (IIa) wherein R₃ is—CH₃, reacting a compound of formula (IVa) analogously to process steps(H1) to (H3); or

(K) for the preparation of a compound of formula (IIa) or (IIb) whereinR₃ is as defined above for formula (I), reacting a compound of formula(IIa) or (IIb) wherein R₃ is H with a compound of the formula Hal-R₃₃wherein R₃₃ is unsubstituted or mono- to penta-substituted C₂-C₁₂alkylor unsubstituted or mono- to penta-substituted C₂-C₁₂alkenyl and Hal ishalogen, preferably iodine or bromine.

Compounds according to the above definition of formulae (IIa) and (IIb)wherein R₃ is H and which are used as intermediates for the preparationof the compounds of formula (I) according to the invention can beprepared by

(L) either reacting a compound of formula (IVb) analogously to processstep (H1) with a phosphine and then with a base; and further reactingthe resulting compound of formula (IIb) analogously to process step (D);or reacting a compound of formula (IIa) analogously to process step (H1)with a phosphine and then with a base.

The invention further relates to a process for the preparation of acompound of formula (I) as defined above, wherein

(M) a compound of formula (IIa) or (IIb) as defined above is reactedwith a compound of the formula R₂—X-Z-T, wherein R₂, X and Z are asdefined for formula (I) and T is a leaving group, and, whereappropriate, the resulting compound of formula

wherein A₁, R₂ and R₃ are as defined above, is further reacted accordingto process variant (D); or

(N) for the preparation of a compound of formula (I) wherein the groupR₂-Z-X— is R₂—NHC(═O)— or R₂—NHC(═S)—, and wherein R₂ is as defined forformula (I), a compound of formula (IIa) or (IIb) as defined above isreacted with a compound of the formula R₂—N═C═O or of the formulaR₂—N═C═S, wherein R₂ is as defined for formula (I), and, whereappropriate, the resulting compound of formula (Ia) wherein the groupR₂-Z-X— is R₂—NHC(═O)— or R₂—NHC(═S)— is further reacted according toprocess variant (D).

The remarks made above regarding tautomers of compounds of formula (I)apply analogously to the starting materials mentioned hereinbefore andhereinafter with regard to their tautomers.

The reactions described hereinbefore and hereinafter are carried out ina manner known per se, for example in the absence or, customarily, inthe presence of a suitable solvent or diluent or of a mixture thereof,the reactions being carried out, as required, with cooling, at roomtemperature or with heating, for example in a temperature range ofapproximately from −80° C. to the boiling temperature of the reactionmedium, preferably from approximately 0° C. to approximately +150° C.,and, if necessary, in a closed vessel, under pressure, under an inertgas atmosphere and/or under anhydrous conditions. Especiallyadvantageous reaction conditions can be found in the Examples.

The reaction time is not critical; a reaction time of from approximately0.1 to approximately 72 hours, especially from approximately 0.5 toapproximately 24 hours, is preferred.

The product is isolated by customary methods, for example by means offiltration, crystallisation, distillation or chromatography, or anysuitable combination of such methods.

The starting materials mentioned hereinbefore and hereinafter that areused for the preparation of the compounds of formula (I) and, whereapplicable, their tautomers are known or can be prepared by methodsknown per se, e.g. as indicated below.

Process Variant (A):

Examples of solvents and diluents include: aromatic, aliphatic andalicyclic hydrocarbons and halogenated hydrocarbons, such as benzene,toluene, xylene, mesitylene, tetralin, chlorobenzene, dichlorobenzene,bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane,trichloromethane, tetrachloromethane, dichloroethane, trichloroethene ortetrachloroethene; ethers, such as diethyl ether, dipropyl ether,diisopropyl ether, dibutyl ether, tert-butyl methyl ether, ethyleneglycol monomethyl ether, ethylene glycol monoethyl ether, ethyleneglycol dimethyl ether, dimethoxydiethyl ether, tetrahydrofuran ordioxane; or mixtures of the mentioned solvents. Dichloromethane ispreferred.

Suitable leaving groups Q in the compounds of formula (III) areespecially sulfonic acid radicals; preference is given, for example, tothe anions of toluenesulfonic acid, methanesulfonic acid,trifluoromethanesulfonic acid, pentafluoroethanesulfonic acid andnonafluorobutanesulfonic acid.

Suitable protecting groups Sa in the compounds of formulae (II), (III),(IV) and (V) are especially trialkylsilyl groups; preference is given,for example, to trimethylsilyl, triethylsilyl, dimethyl-tert-butylsilyl,dimethyl-isopropylsilyl, dimethyl-1,1,2-trimethylpropylsilyl,diethyl-isopropylsilyl, dimethyl-tert-hexylsilyl, but alsophenyl-tert-alkylsilyl groups, such as diphenyl-tert-butylsilyl; orallyloxycarbonyl.

The reactions are advantageously carried out in a temperature range offrom approximately −70° C. to +10° C., preferably at from −35° C. to 0°C.

Especially preferred conditions for the reaction are described inExample P.1.

Process Variant (B):

Examples of solvents and diluents include: nitriles, such asacetonitrile; dimethyl sulfoxide; and alcohols, such as, for example,ethanol or methanol; amides, such as dimethylformamide ordimethylacetamide, are especially suitable.

Suitable azide salts are especially NaN₃ and Zn(N₃)₂; especially NaN₃.

The reactions are advantageously carried out in a temperature range offrom −10° C. to +10° C.

Especially preferred conditions for the reaction are to be found, forexample, in Example P.1.

Process Variant (C):

Examples of solvents and diluents are the same as those mentioned underProcess variant (A). In addition, amides, for example, such asdimethylformamide or hexamethylphosphorus triamide, are also suitable.

Suitable azodicarboxylic acid derivatives are especially azodicarboxylicacid esters, for example the dibenzyl, diethyl, dibutyl, diisopropyl ordi-tert-butyl ester or the di-(2,2,2-trichloroethyl) ester; orazodicarboxylic acid amides, such as, for example,N,N,N,N-azodicarboxylic acid tetramethylamide or azodicarboxylic aciddimorpholide.

Suitable azide donors are especially (PhO)₂PN₃, Zn(N₃)₂.pyridine or HN₃.

Suitable phosphines are especially trialkyl- and triaryl-phosphines,such as, for example, trimethylphosphine, triethylphosphine andtri-n-butylphosphine, and triphenylphosphine.

The reactions are advantageously carried out in a temperature range offrom −20° C. to 150° C.

Process Variant (D):

Examples of solvents and diluents are the same as those mentioned underProcess variant (A). In addition, nitriles, such as acetonitrile;dimethyl sulfoxide; and alcohols, such as, for example, ethanol ormethanol; and water are suitable.

The reactions are advantageously carried out in a temperature range offrom −10° C. to +25° C.

Suitable acids for the removal of the protecting group are, for example,HF in pyridine, Zn(BF₄)₂.H₂O or methanesulfonic acid.

Process Variants (E, L):

Examples of solvents and diluents are the same as those mentioned underProcess variant (A). In addition, nitriles, such as acetonitrile; andesters of carboxylic acids, such as, for example, ethyl acetate, aresuitable.

The reactions are advantageously carried out in a temperature range offrom 0° C. to +100° C.

Suitable phosphines are inter alia the same as those mentioned underProcess variant (C). Suitable phosphites are, for example, trimethylphosphite, triethyl phosphite, tri-n-butyl phosphite and tri-tert-butylphosphite.

Suitable hydrides are, especially, complex hydrides, especially sodiumborohydride and sodium cyanoborohydride.

Suitable acids are, especially, weak carboxylic acids, such as aceticacid, propionic acid or pivalic acid; especially pivalic acid. The acidsare used especially in catalytic amounts; especially in amounts below 10mol %, more especially below 5 mol %, most especially below 2 mol %.

Especially preferred conditions for this process variant are described,for example, in Example P.3.

Process Variant (F):

The same process conditions as those described in variant (D) apply. Thereaction is preferably carried out in the presence of methanesulfonicacid in methanol at 0° C.

Process Variant (G):

The same process conditions as those described in variant (E) apply.

Process Variant (H):

The same process conditions as those described in variant (E) apply. Thephosphine used is, for example, trimethylphosphine or tributylphosphine,preferably trimethylphosphine.

Process Variant (I):

The same process conditions as those described in variant (H) apply.

Process Variant (K):

The same solvents as those indicated under Process variant (A) are used.In addition, amides, such as dimethylformamide and dimethylacetamide;nitriles, such as acetonitrile; and esters, such as ethyl acetate, arealso suitable.

Suitable bases are especially carbonates, such as sodium carbonate,sodium hydrogen carbonate, potassium carbonate, trialkylamines, such astriethylamine, and heterocyclic bases, such as, for example, pyridine.

Process Variant (L):

Suitable solvents and diluents are the same as those mentioned underProcess variant (A). In addition, nitrites, such as acetonitrile; andesters of carboxylic acids, such as, for example, ethyl acetate, aresuitable.

Suitable phosphines are especially trialkyl- and triaryl-phosphines,such as, for exam-ple, trimethylphosphine and tri-n-butylphosphine andalso triphenylphosphine.

There are used as bases especially sodium hydroxide solution or ammonia,especially in highly dilute form, especially, for example, in aconcentration of 0.01 N.

Process Variant (M):

Suitable leaving groups are especially halogens, especially bromine orchlorine.

Suitable solvents are those which are inert under the reactionconditions; these include especially those mentioned under Processvariant (A).

The procedure is carried out at temperatures of from 0° C. to theboiling point of the respective solvent.

Suitable bases are especially carbonates, such as sodium carbonate,sodium hydrogen carbonate or potassium carbonate, trialkylamines, suchas triethylamine, and heterocyclic bases, such as, for example,pyridine.

Process Variant (N):

Suitable solvents are those which are inert under the reactionconditions; these include especially those mentioned under Processvariant (A).

The procedure is carried out at temperatures of from 0° C. to theboiling point of the respective solvent, especially at from 20° C. to40° C.

The compounds of formula (I) may be in the form of one of the possibleisomers or in the form of a mixture thereof, in the form of pure isomersor in the form of an isomeric mixture, i.e. in the form of adiastereomeric mixture; the invention relates both to the pure isomersand to the diastereomeric mixtures and is to be interpreted accordinglyhereinabove and hereinbelow, even i stereochemical details are notmentioned specifically in every case.

The diastereomeric mixtures can be resolved into the pure isomers byknown methods, for example by recrystallisation from a solvent, bychromatography, for example high pressure liquid chromatography (HPLC)on acetylcellulose, with the aid of suitable microorganisms, by cleavagewith specific, immobilised enzymes, or via the formation of inclusioncompounds, for example using crown ethers, only one isomer beingcomplexed.

Apart from by separation of corresponding mixtures of isomers, purediastereoisomers can be obtained according to the invention also bygenerally known methods of stereoselective synthesis, for example bycarrying out the process according to the invention using startingmaterials having correspondingly suitable stereochemistry.

In each case it is advantageous to isolate or synthesise thebiologically more active isomer, where the individual components havedifferent biological activity.

The compounds of formula (I) may also be obtained in the form of theirhydrates and/or may include other solvents, for example solvents whichmay have been used for the crystallisation of compounds in solid form.

The invention relates to all those embodiments of the process accordingto which a compound obtainable as starting material or intermediate atany stage of the process is used as starting material and all or some ofthe remaining steps are carried out, or in which a starting material isused in the form of a derivative and/or a salt and/or its diastereomers,or, especially, is formed under the reaction conditions. For instancecompounds of formula (I) bearing a functional group in its free orprotected form can be used as starting materials for the preparation offurther compounds of formula (I). For such manipulations methods knownto the person skilled in the art can be applied.

In the processes of the present invention it is preferable to use thosestarting materials and intermediates which result in the compounds offormula (I) that are especially preferred.

The invention relates especially to the preparation processes describedin the Examples.

In the area of pest control, the compounds of formula (I) according tothe invention are active ingredients exhibiting valuable preventiveand/or curative activity with a very advantageous biocidal spectrum anda very broad spectrum, even at low rates of concentration, while beingwell tolerated by warm-blooded animals, fish and plants. They are,surprisingly, equally suitable for controlling both plant pests andecto- and endo-parasites in humans and more especially in productivelivestock, domestic animals and pets. They are effective against all orindividual development stages of normally sensitive animal pests, butalso of resistant animal pests, such as insects and members of the orderAcarina, nematodes, cestodes and trematodes, while at the same timeprotecting useful organisms. The insecticidal or acaricidal activity ofthe active ingredients according to the invention may manifest itselfdirectly, i.e. in the mortality of the pests, which occurs immediatelyor only after some time, for example during moulting, or indirectly, forexample in reduced oviposition and/or hatching rate, good activitycorresponding to a mortality of at least 50 to 60%.

The action of the compounds according to the invention and thecompositions comprising them against animal pests can be significantlybroadened and adapted to the given circumstances by the addition ofother insecticides, acaricides or nematicides. Suitable additivesinclude, for example, representatives of the following classes of activeingredient: organophosphorus compounds, nitrophenols and derivatives,formamidines, ureas, carbamates, pyrethroids, chlorinated hydrocarbons,neonicotinoids and Bacillus thuringiensis preparations.

Examples of especially suitable mixing partners include: azamethiphos;chlorfenvinphos; cypermethrin, cypermethrin high-cis; cyromazine;diafenthiuron; diazinon; dichlorvos; dicrotophos; dicyclanil;fenoxycarb; fluazuron; furathiocarb; isazofos; iodfenphos; kinoprene;lufenuron; methacriphos; methidathion; monocrotophos; phosphamidon;profenofos; diofenolan; a compound obtainable from the Bacillusthuringiensis strain GC91 or from strain NCTC11821; pymetrozine;bromopropylate; methoprene; disulfoton; quinalphos; tau-fluvalinate;thiocyclam; thiometon; aldicarb; azinphos-methyl; benfuracarb;bifenthrin; buprofezin; carbofuran; dibutylaminothio; cartap;chlorfluazuron; chlorpyrifos; cyfluthrin; lambda-cyhalothrin;alpha-cypermethrin; zeta-cypermethrin; deltamethrin; diflubenzuron;endosulfan; ethiofencarb; fenitrothion; fenobucarb; fenvalerate;formothion; methiocarb; heptenophos; imidacloprid; isoprocarb;methamidophos; methomyl; mevinphos; parathion; parathion-methyl;phosalone; pirimicarb; propoxur; teflubenzuron; terbufos; triazamate;fenobucarb; tebufenozide; fipronil; beta-cyfluthrin; silafluofen;fenpyroximate; pyridaben; fenazaquin; pyriproxyfen; pyrimidifen;nitenpyram; acetamiprid; avermectin B1 (abamectin); emamectin;emamectinbenzoate; spinosad; a plant extract that is active againstinsects; a preparation that comprises nematodes and is active againstinsects; a preparation obtainable from Bacillus subtilis; a preparationthat comprises fungi and is active against insects; a preparation thatcomprises viruses and is active against insects; chlorfenapyr; acephate;acrinathrin; alanycarb; alphamethrin; amitraz; AZ 60541; azinphos A;azinphos M; azocyclotin; bendiocarb; bensultap; beta-cyfluthrin; BPMC;brofenprox; bromophos A; bufencarb; butocarboxim; butylpyridaben;cadusafos; carbaryl; carbophenothion; chloethocarb; chlorethoxyfos;chlormephos; cisresmethrin; clocythrin; clofentezine; cyanophos;cycloprothrin; cyhexatin; demeton M; demeton S; demeton-S-methyl;dichlofenthion; dicliphos; diethion; dimethoate; dimethylvinphos;dioxathion; edifenphos; esfenvalerate; ethion; ethofenprox; ethoprophos;etrimphos; fenamiphos; fenbutatin oxide; fenothiocarb; fenpropathrin;fenpyrad; fenthion; fluazinam; flucycloxuron; flucythrinate;flufenoxuron; flufenprox; fonophos; fosthiazate; fubfenprox; HCH;hexaflumuron; hexythiazox; IKI-220; iprobenfos; isofenphos; isoxathion;ivermectin; malathion; mecarbam; mesulfenphos; metaldehyde; metolcarb;milbemectin; moxidectin; naled; NC 184; omethoate; oxamyl; oxydemethonM; oxydeprofos; permethrin; phenthoate; phorate; phosmet; phoxim;pirimiphos M; pirimiphos E; promecarb; propaphos; prothiofos; prothoate;pyrachlophos; pyradaphenthion; pyresmethrin; pyrethrum; tebufenozide;salithion; sebufos; sulfotep; suiprofos; tebufenpyrad; tebupirimphos;tefluthrin; temephos; terbam; tetrachlorvinphos; thiacloprid; thiafenox;thiodicarb; thiofanox; thionazin; thuringiensin; tralomethrin;triarthene; triazophos; triazuron; trichlorfon; triflumuron;trimethacarb; vamidothion; xylylcarb; YI 5301/5302; zetamethrin;DPX-MP062—indoxacarb; methoxyfenozide; bifenazate; XMC (3,5-xylylmethylcarbamate); or the fungus pathogen Metarhizium anisopliae; mostespecially fipronil, thiamethoxam, or lambda-cyhalothrin.

The said animal pests include, for example, those mentioned in EuropeanPatent Application EP-A-736 252, page 5, line 55, to page 6, line 55.The pests mentioned therein are therefore included by reference in thesubject matter of the present invention.

It is also possible to control pests of the class Nematoda using thecompounds according to the invention. Such pests include, for example,

root knot nematodes, cyst-forming nematodes and also stem and leafnematodes;

especially of Heterodera spp., e.g. Heterodera schachtii, Heterodoraavenae and Heterodora trifolii; Globodera spp., e.g. Globoderarostochiensis; Meloidogyne spp., e.g. Meloidogyne incognita andMeloidogyne javanica; Radopholus spp., e.g. Radopholus similis;Pratylenchus, e.g. Pratylenchus neglectans and Pratylenchus penetrans;Tylenchulus, e.g. Tylenchulus semipenetrans; Longidorus, Trichodorus,Xiphinema, Ditylenchus, Apheenchoides and Anguina; especiallyMeloidogyne, e.g. Meloidogyne incognita, and Heterodera, e.g. Heteroderaglycines.

An especially important aspect of the present invention is the use ofthe compounds of formula (I) according to the invention in theprotection of plants against parasitic feeding pests.

The compounds according to the invention can be used to control, i.e. toinhibit or destroy, pests of the mentioned type occurring on plants,especially on useful plants and ornamentals in agriculture, inhorticulture and in forestry, or on parts of such plants, such as thefruits, blossoms, leaves, stems, tubers or roots, while in some casesplant parts that grow later are still protected against those pests.

Target crops include especially cereals, such as wheat, barley, rye,oats, rice, maize and sorghum; beet, such as sugar beet and fodder beet;fruit, e.g. pomes, stone fruit and soft fruit, such as apples, pears,plums, peaches, almonds, cherries and berries, e.g. strawberries,raspberries and blackberries; leguminous plants, such as beans, lentils,peas and soybeans; oil plants, such as rape, mustard, poppy, olives,sunflowers, coconut, castor oil, cocoa and groundnuts; cucurbitaceae,such as marrows, cucumbers and melons; fibre plants, such as cotton,flax, hemp and jute; citrus fruits, such as oranges, lemons, grapefruitand mandarins; vegetables, such as spinach, lettuce, asparagus,brassicas, carrots, onions, tomatoes, potatoes and paprika; lauraceae,such as avocado, cinnamon and camphor; and tobacco, nuts, coffee,aubergines, sugar cane, tea, pepper, vines, hops, bananas, naturalrubber plants and ornamentals.

Further areas of use of the compounds according to the invention are theprotection of stored goods and storerooms and the protection of rawmaterials, and also in the hygiene sector, especially the protection ofdomestic animals and productive livestock against pests of the mentionedtype, more especially the protection of domestic animals, especiallycats and dogs, from infestation by fleas, ticks and nematodes.

The invention therefore relates also to pesticidal compositions, such asemulsifiable concentrates, suspension concentrates, directly sprayableor dilutable solutions, spreadable pastes, dilute emulsions, wettablepowders, soluble powders, dispersible powders, wettable powders, dusts,granules and encapsulations of polymer substances, that comprise atleast one of the compounds according to the invention, the choice offormulation being made in accordance with the intended objectives andthe prevailing circumstances.

The active ingredient is used in those compositions in pure form, asolid active ingredient, for example, in a specific particle size, orpreferably together with at least one of the adjuvants customary informulation technology, such as extenders, e.g. solvents or solidcarriers, or surface-active compounds (surfactants). In the area ofparasite control in humans, domestic animals, productive livestock andpets it will be self-evident that only physiologically tolerableadditives are used.

As formulation adjuvants there are used, for example, solid carriers,solvents, stabilisers, “slow release” adjuvants, colourings andoptionally surface-active substances (surfactants). Suitable carriersand adjuvants include all substances customarily used. As adjuvants,such as solvents, solid carriers, surface-active compounds, non-ionicsurfactants, cationic surfactants, anionic surfactants and furtheradjuvants in the compositions used according to the invention, therecome into consideration, for example, those described in EP-A-736 252,page 7, line 51 to page 8, line 39.

The compositions for use in crop protection and in humans, domesticanimals and productive livestock generally comprise from 0.1 to 99%,especially from 0.1 to 95%, of active ingredient and from 1 to 99.9%,especially from 5 to 99.9%, of at least one solid or liquid adjuvant,the composition generally including from 0 to 25%, especially from 0.1to 20%, of surfactants (%=% by weight in each case). Whereas commercialproducts will preferably be formulated as concentrates, the end userwill normally employ dilute formulations having considerably lowerconcentrations of active ingredient.

Preferred crop protection products have especially the followingcompositions (%=percent by weight):

Emulsifiable concentrates: active ingredient:   1 to 90%, preferably 5to 20% surfactant:   1 to 30%, preferably 10 to 20% solvent:   5 to 98%,preferably 70 to 85% Dusts: active ingredient:  0.1 to 10%, preferably0.1 to 1% solid carrier: 99.9 to 90%, preferably 99.9 to 99% Suspensionconcentrates: active ingredient:   5 to 75%, preferably 10 to 50% water:  94 to 24%, preferably 88 to 30% surfactant:   1 to 40%, preferably 2to 30% Wettable powders: active ingredient:  0.5 to 90%, preferably 1 to80% surfactant:  0.5 to 20%, preferably 1 to 15% solid carrier:   5 to99%, preferably 15 to 98% Granules: active ingredient:  0.5 to 30%,preferably 3 to 15% solid carrier: 99.5 to 70%, preferably 97 to 85%

The compositions according to the invention may also comprise furthersolid or liquid adjuvants, such as stabilisers, e.g. vegetable oils orepoxidised vegetable oils (e.g. epoxidised coconut oil, rapeseed oil orsoybean oil), antifoams, e.g. silicone oil, preservatives, viscosityregulators, binders and/or tackifiers as well as fertilisers or otheractive ingredients for obtaining special effects, e.g. acaricides,bactericides, fungicides, nematicides, molluscicides or selectiveherbicides.

The crop protection products according to the invention are prepared inknown manner, in the absence of adjuvants, e.g. by grinding, sievingand/or compressing a solid active ingredient or mixture of activeingredients, for example to a certain particle size, and in the presenceof at least one adjuvant, for example by intimately mixing and/orgrinding the active ingredient or mixture of active ingredients with theadjuvant(s). The invention relates likewise to those processes for thepreparation of the compositions according to the invention and to theuse of the compounds of formula (I) in the preparation of thosecompositions.

The invention relates also to the methods of application of the cropprotection products, i.e. the methods of controlling pests of thementioned type, such as spraying, atomising, dusting, coating, dressing,scattering or pouring, which are selected in accordance with theintended objectives and the prevailing circumstances, and to the use ofthe compositions for controlling pests of the mentioned type. Typicalrates of concentration are from 0.1 to 1000 ppm, preferably from 0.1 to500 ppm, of active ingredient. The rates of application per hectare aregenerally from 1 to 2000 g of active ingredient per hectare, especiallyfrom 10 to 1000 g/ha, preferably from 20 to 600 g/ha.

A preferred method of application in the area of crop protection isapplication to the foliage of the plants (foliar application), thefrequency and the rate of application being dependent upon the risk ofinfestation by the pest in question. However, the active ingredient canalso penetrate the plants through the roots (systemic action) when thelocus of the plants is impregnated with a liquid formulation or when theactive ingredient is incorporated in solid form into the locus of theplants, for example into the soil, e.g. in granular form (soilapplication). In the case of paddy rice crops, such granules may beapplied in metered amounts to the flooded rice field.

The crop protection products according to the invention are alsosuitable for protecting plant propagation material, e.g. seed, such asfruits, tubers or grains, or plant cuttings, against animal pests. Thepropagation material can be treated with the composition beforeplanting: seed, for example, can be dressed before being sown. Theactive ingredients according to the invention can also be applied tograins (coating), either by impregnating the seeds in a liquidformulation or by coating them with a solid formulation. The compositioncan also be applied to the planting site when the propagation materialis being planted, for example to the seed furrow during sowing. Theinvention relates also to such methods of treating plant propagationmaterial and to the plant propagation material so treated.

PREPARATION EXAMPLES

In the following Examples, the preparation of avermectin B1 derivatives(mixtures of avermectin B1a and B1b derivative) is described. The B1bderivative generally represents about only from 5 to 10% by weight ofthe mixtures and, for that reason, usually only the bands of the B1aderivative can be detected in the NMR spectrum.

The abbreviations used in the NMR data information have the followingmeanings:

s: singlet; MHz: megahertz; brs: broad singlet; t: triplet; m:multiplet; d: doublet; J: coupling constant.

TBDMS in the Examples represents the radical —Si(CH₃)₂(tert-butyl), R₁ amixture of isopropyl and sec-butyl.

Since the compounds are in most cases in the form of mixtures of theavermectin B1a and B1b derivative, characterisation by means of thecustomary physical data such as melting point or refractive index is oflittle use. For that reason, the compounds are characterised by means ofNMR spectroscopy following purification by chromatography, or byreference to the retention times determined in analysis by means of HPLC(high-resolution liquid chromatography), as indicated in the aboveExamples. The term “B1a” in the formulae of the following Examples andTables refers to the main component, wherein RI is sec-butyl, with acontent usually greater than 80%. “B1b” represents the secondarycomponent, wherein R₁ is isopropyl. In the case of the compounds forwhich a retention time is given only in the B1a column, it is notpossible to determine the retention time for the B1b component owing tothe small proportion of B1b derivative. Allocation of the correctstructures of the B1a and B1b components is carried out by massspectrometry.

The following method is used for the HPLC analysis in Tables unlessotherwise stated:

HPLC gradient conditions solvent A: 0.01% trifluoroacetic acid in H₂Osolvent B: 0.01% trifluoroacetic acid in CH₃CN flow rate Time [min] A[%] B [%] [μl/min]  0 80  20 500  0.1 50  50 500 10  5  95 500 15  0 100500 17  0 100 500 17.1 80  20 500 22 80  20 500 column: YMC-Pack ODS-AQcolumn length: 125 mm column internal diameter:  2 mm temperature: 40°C.The YMC-Pack ODS-AQ column used for chromatography of the compounds isproduced by the company YMC, Alte Raesfelderstrasse 6, 46514 Schermbeck,Germany.

Example P.1 Preparation of 4″-deoxy-4″-(S)-formylamino-avermectin B₁ offormula

0.05 ml of formic acid-acetic acid anhydride is added to a solution of100 mg (0.115 mmol) of 4″-deoxy-4″-(S)-amino-avermectin B₁ in 4 ml ofTHF at room temperature and the mixture is left to stand for 15 hours.For working-up, the mixture is poured onto water and extracted threetimes with ethyl acetate. The combined organic phases are washed withsaturated NaCl solution and dried over Na₂SO₄. The crude product ispurified on silica gel in CH₂Cl₂/MeOH (9:1). After drying under a highvacuum, 4″-deoxy-4″-(S)-formylamino-avermectin B₁ is thus obtained as amixture of rotational isomers that exhibits the following signals in theLC-MS analysis: t_(RT): B_(1a): 7.80 min (88.3%), 900.5 (M+H), B1b: 7.00min (11.7%), 908.4 (M+Na) (compound 1.001).

Example P.2 Preparation of4″-deoxy-4″-(S)—N-methyl-acetylamino-avermectin B₁ of formula

A vigorously stirred two-phase solution consisting of 100 mg of4″-deoxy-4″-(S)—N-methyl-amino-avermectin B₁ in 5 ml of ethyl acetateand 11.3 ml of saturated NaHCO₃ solution is treated with 115 mg ofacetic anhydride for 60 hours at 70° C. under argon. Aqueous working-upwith ethyl acetate and purification on silica gel in ethylacetate/hexane (5:1) yield4″-deoxy-4″-(S)—N-methyl-acetylamino-avermectin B₁ as a mixture ofrotational isomers that exhibits the following signals in the LC-MSanalysis: t_(RT): B_(1a): 8.80 min (broad, 100%), 928.7 (M+H),B_(1b):8.16 min (compound 1.002).

Example P.3 Preparation of4″-deoxy-4″-(S)—N-methyl-methoxycarbonylamino-avermectin B₁ of formula

A vigorously stirred two-phase solution consisting of 100 mg of4″-deoxy-4″-(S)—N-methyl-amino-avermectin B₁ in 5 ml of ethyl acetateand 11.3 ml of saturated NaHCO₃ solution is treated with 0.087 ml ofchloroformic acid methyl ester for 3 hours at 65° C. under an argonatmosphere. Aqueous working-up with ethyl acetate followed bypurification by chromatography on silica gel in ethyl acetate/hexane(1:1) yields 4″-deoxy-4″-(S)—N-methyl-methoxycarbonylamino-avermectin B₁as a mixture of rotational isomers that exhibits the following signalsin the LC-MS analysis: t_(RT): B_(1a): 10.09 min (86.7%), 966.5 (M+Na),B_(1b): 8.97 min (8.5%): 952.4 (M+Na) (compound 1.003).

Example P.4 Preparation of4″-deoxy-4″-(S)—N-methyl-methoxyacetylamino-avermectin B₁ of formula

A vigorously stirred two-phase solution consisting of 100 mg of4″-deoxy-4″-(S)—N-methyl-amino-avermectin B₁ in 5 ml of ethyl acetateand 11.3 ml of saturated NaHCO₃ solution is treated with 0.103 ml ofmethoxyacetyl chloride for 12 hours at 70° C. under an argon atmosphere.Aqueous working-up with ethyl acetate followed by purification bychromatography on silica gel in CH₂Cl₂/MeOH (95:5) yields4″-deoxy-4″-(S)—N-methyl-methoxyacetyl-amino-avermectin B1 as a mixtureof rotational isomers that exhibits the following signals in the LC-MSanalysis: t_(RT): B_(1a): 8.58-8.70 min (92.7%), 980 (M+Na), B_(1b):8.22 min (7.3%), 966.5 (M+Na) (compound 1.004).

Example P.5

In an analogous manner, the compounds of the following Tables 1A to 1Fwere prepared. In the tables, the symbol

indicates the bond by which the radical in question is bonded theremainder of the molecule.

TABLE 1A Compounds of the formula

LC-MS: t_(RT) No. R_(a) B_(1a)(min) B_(1b)(min) 1A.005 H 8.58 8.301A.006 phenyl 10.62 9.56 1A.007

10.73 9.66 1A.008

9.44 8.69

TABLE 1B Compounds of the formula

LC-MS: t_(RT) No. R₂ B_(1a)(min) B_(1b)(min) 1B.1

10.2 1B.2

9.8 9.2 1B.3

10.2 1B.4

9.4 8.8 1B.5

10.8 10.1 1B.6

11.7 1B.7

11.3 10.6 1B.8

10.6 9.9 1B.9

9.9 9.1  1B.10

9.5 8.7

TABLE 1C Compounds of the formula

LC-MS: t_(RT) No. R₂ B_(1a)(min) B_(1b)(min) 1C.1 Ethyl 11.2 10.5

TABLE 1D Compounds of the formula

LC-MS: t_(RT) No. R₂ B_(1a)(min) B_(1b)(min) 1D.1

11.6 11.0 1D.2

10.7 — 1D.3

11.0 1D.4

— — 1D.5

— — 1D.6

12.5 12.0 1D.7

11.9 11.2 1D.8

— — 1D.9

11.0 10.4  1D.10

— —  1D.11

— —  1D.12

— —

TABLE 1E Compounds of the formula

HPLC gradient conditions Solvent A (%): 45.0 H₂O (containing 0.1%trifluorocetic acid and 10% CH₃CN) Solvent B (%): 55.0 CH₃CN (containing0.1% trifluorocetic acid) Solvent C (%): CH₃OH Time [min] A [%] B [%] C[%] flow rate [ml/min] 0.00 45 55  0 3.50 3.50  0 90 10 3.50 3.80  0 9010 3.50 4.00 45 55 10 3.50 Column: YMC CombiScreen ODS-AQ Column length: 30 mm Column internal diameter: 4.6 mm temperature: 40° C. LC-MS:t_(RT) No. R_(a) B_(1a)(min) B_(1b)(min) 1E.1 

2.20 2.00 1E.2 

2.70 2.32 1E.3 

2.20 2.07 1E.4 

2.20 1.98 1E.5 

2.30 1.98 1E.6 

2.40 2.03 1E.7 

2.50 2.11 1E.8 

2.60 2.23 1E.9 

2.80 2.40 1E.10

1.70 1.30 1E.11

2.10 2.04 1E.12

2.20 2.03 1E.13

2.30 2.03 1E.14

2.70 2.20 1E.15

2.60 2.20 1E.16

2.50 2.00 1E.17

1.70 1.70 1E.18

2.60 2.20 1E.19

2.40 2.19 1E.20

2.10 1.69 1E.21

2.40 1.94 1E.22

1.80 1.30 1E.23

1.60 1.40 1E.24

2.20 1.94 1E.25

2.40 2.07 1E.26

2.70 2.40 1E.27

1.60 1.60 1E.28

2.70 2.57 1E.29

2.40 1.94 1E.30

2.70 2.44 1E.31

2.70 2.19 1E.32

2.70 2.07 1E.33

2.40 2.03 1E.34

2.70 1.90 1E.35

1.4 1.4 1E.36

2.40 1.90 1E.37

2.50 2.03 1E.38

1.80 1.80 1E.39

2.70 2.19 1E.40

2.20 1.90

TABLE 1F Compounds of the formula

HPLC gradient conditions solvent A (%): 40.0 H₂O (containing 0.1% HCO₂H)solvent B (%): 60.0 CH₃CN (containing 0.1% HCO₂H) Time [min] A [%] B [%]flow rate [ml/min] 0.00 40 60 3.50 3.50 0 100 3.50 3.80 0 100 3.50 4.0040 60 3.50 column: YMC CombiScreen ODS-AQ column length:  30 mm columninternal diameter: 4.6 mm temperature: 40° C. LC-MS: t_(RT) No. R_(a)B_(1a) (min) B_(1b) (min) 1F.1

1.9 1.6 1F.2

2.1 1.9 1F.3

1.5 1.3 1F.4

1.8 1.5 1F.5

1.8 1.5 1F.6

1.4 1.2 1F.7

2.2 1.9 1F.8

1.9 1.7 1F.9

1.9 1.6 1F.10

1.6 1.4 1F.11

1.9 1.7 1F.12

2.0 1.8 1F.13

2.1 1.9 1F.14

2.2 1.9 1F.15

1.7 1.5 1F.16

1.2 1.0 1F.17

1.8 1.5 1F.18

1.9 1.6 1F.19

1.9 1.7 1F.20

1.6 1.4 1F.21

1.9 1.7 1F.22

1.9 1.7 1F.23

1.5 1.2 1F.24

1.4 1.2 1F.25

1.5 1.3 1F.26

2.0 1.7 1F.27

1.9 1.7 1F.28

1.5 1.2 1F.29

2 1.7 1F.30

1.8 1.6 1F.31

1.9 1.7 1F.32

2.0 1.8 1F.33

2.0 1.7 1F.34

1.7 1F.35

1.5 1.3 1F.36

1.3 1F.37

1.9 1.6 1F.38

1.7 1.5 1F.39

2.2 1.9 1F.40

1.5 1.3 1F.41

1.7 1.4 1F.42

2.1 1.8 1F.43

1.5 1.3 1F.44

1.9 1.7 1F.45

1.6 1.4 1F.46

2.4 2.1 1F.47

1.5 1.3 1F.48

1.9 1.7 1F.49

1.8 1.5 1F.50

1.3 1.1 1F.51

2.2 1.9 1F.52

2.7 2.4 1F.53

1.8 1.5 1F.54

2.0 1.7 1F.55

1.9 1.6 1F.56

2.1 1.8 1F.57

1.7 1.5 1F.58

1.7 1.5 1F.59

1.9 1.6 1F.60

1.7 1.5 1F.61

1.9 1.7 1F.62

2.0 1.8 1F.63

2.2 1.9 1F.64

2.0 1.7

Analogously to the above Preparation Examples, the compounds listed inTables 2 and to 71 can also be prepared. In Table A, the symbol

 indicates the bond by which the radical in question is bonded to Z.

TABLE A Compounds of general formula (I) wherein R₁, R₃, X and Z are asdefined in formula (I) and the bond between carbon atoms 22 and 23 is adouble bond No. R₂ A.1 H A.2 Phenyl A.3 CH₃—O—CH₂— A.4 Methyl A.5

A.6 Ethyl A.7

A.8

A.9 Cyclopropyl A.10 Isopropyl A.11 n-propyl A.12 n-butyl A.13

A.14 Cyclobutyl A.15

A.16 Isopropyl A.17

A.18

A.19

A.20 Cyclopentyl A.21

A.22

A.23

A.24 n-hexyl A.25 t-butyl A.26

A.27

A.28

A.29

A.30

A.31 2-Cl-ethyl A.32 Cyclohexyl A.33

A.34 n-heptyl A.35

A.36

A.37

A.38

A.39

A.40

A.41

A.42

A.43

A.44

A.45

A.46

A.47

A.48

A.49

A.50

A.51

A.52

A.53

A.54

A.55

A.56

A.57

A.58 n-octyl A.59

A.60

A.61

A.62

A.63

A.64

A.65

A.66

A.67

A.68

A.69

A.70

A.71

A.72

A.73

A.74

A.75

A.76

A.77

A.78

A.79

A.80

A.81

A.82

A.83

A.84

A.85

A.86

A.87

A.88

A.89

A.90

A.91

A.92

A.93

A.94

A.95

A.96

A.97

A.98

A.99

A.100

A.101

A.102

A.103

A.104

A.105

A.106

A.107

A.108

A.109

A.110

A.111

A.112

A.113

A.114

A.115

A.116

A.117

A.118

A.119

A.120

A.121

A.122

A.123

A.124

A.125

A.126

A.127

A.128

A.129

A.130

A.131

A.132

A.133

A.134

A.135

A.136

A.137

A.138

A.139

A.140

A.141

A.142

A.143

A.144

A.145

A.146

A.147

A.148

A.149

A.150

A.151

A.152

A.153

A.154

A.155

A.156

A.157

A.158

A.159

A.160

A.161

A.162

A.163

A.164

A.165

A.166

A.167

A.168

A.169

A.170

A.171

A.172

A.173

A.174

A.175

A.176

A.177

A.178

A.179 (C₂H₅O)₃Si—CH₂—CH₂—CH₂— A.180 CCl₃— A.181

A.182

A.183

Table 2: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O), X is a bond and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 3: Compounds of formula (I) wherein R₁ is sec-butyl (Bla) oriso-propyl (B1b), Z is —C(═O), X is a bond and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 4: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O), X is a bond and R₃ is ethyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 5: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O), X is a bond and R₃ is n-propyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 6: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is a bond and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 7: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is a bond and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 8: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O), X is NH and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 9: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O), X is NH and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 10: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is O and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 11: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is O and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 12: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O), X is O and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 13: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O), X is O and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 14: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is NH and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 15: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is NH and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 16: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —S(═O)₂—, X is a bond and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 17: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —S(═O)₂—, X is a bond and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 18: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —S(═O)₂—, X is a bond and R₃ is ethyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 19: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —S(═O)₂—, X is NH and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 20: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —S(═O)₂—, X is NCH₃ and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 21: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O)—, X is S, R₃ is H, and the substituent R₂for a compound corresponds to any one of lines A.1 to A.183 of Table A.

Table 22: Compounds of formula (I) wherein R₁ is sec-butyl (B₁a) oriso-propyl (B1b), Z is —C(═O)—, X is S, R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 23: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O)—, X is NCH₃, R₃ is H, and the substituentR₂ for a compound corresponds to any one of lines A.1 to A.183 of TableA.

Table 24: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O)—, X is NCH₃, R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 25: Compounds of formula (1) wherein R₁ is cyclohexyl, Z is C(═O),X is a bond and R₃ is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 26: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O), X is a bond and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 27: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O), X is a bond and R₃ is ethyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 28: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O), X is a bond and R₃ is n-propyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 29: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is C(═S),X is a bond and R₃ is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 30: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is a bond and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 31: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O), X is NH and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 32: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O), X is NH and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 33: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is O and R₃ is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 34: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is O and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 35: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O), X is O and R₃ is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 36: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O), X is O and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 37: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is NH and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 38: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is NH and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 39: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—S(═O)₂—, X is a bond and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 40: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—S(═O)₂—, X is a bond and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 41: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—S(═O)₂—, X is a bond and R₃ is ethyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 42: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—S(═O)₂—, X is NH and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 43: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—S(═O)₂—, X is NCH₃ and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 44: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O)—, X is S, R₃ is H, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 45: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O)—, X is S, R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 46: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O)—, X is NCH₃, R₃ is H, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 47: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O)—, X is NCH₃, R₃ is CH₃, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 48: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O), X is a bond and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 49: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O), X is a bond and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 50: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O), X is a bond and R₃ is ethyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 51: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O), X is a bond and R₃ is n-propyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 52: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is a bond and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 53: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is a bond and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 54: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—O(═O), X is NH and R₃is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 55: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O), X is NH and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 56: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is O and R₃is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 57: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is O and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 58: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O), X is O and R₃ is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 59: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O), X is O and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 60: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is NH and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 61: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is NH and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 62: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—S(═O)₂—, X is a bond and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 63: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—S(═O)₂—, X is a bond and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 64: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—S(═O)₂—, X is a bond and R₃ is ethyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 65: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—S(═O)₂—, X is NH and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 66: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—S(═O)₂—, X is NCH₃ and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 67: Compounds of formula (I) wherein R. is 1-methyl-butyl, Z is—C(═O)—, X is S, R₃ is H, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 68: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O)—, X is S, R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 69: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O)—, X is NCH₃, R₃ is H, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 70: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O)—, X is NCH₃, R₃ is CH₃, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 71: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is C(═S), X is NCH₃ and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 72: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is NCH₃ and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 73: Compounds of formula (I) wherein R: is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is S and R₃ is hydrogen, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 74: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S), X is S and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 75: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —S(═O)₂—, X is NH and R₃ is methyl, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 76: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —S(═O)₂—, X is NCH₃ and R₃ is H, and thesubstituent R₂ for a compound corresponds to any one of lines A.1 toA.183 of Table A.

Table 77: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is NCH₃ and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 78: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is NCH₃ and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 79: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is S and R₃ is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 80: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S), X is S and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 81: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—S(═O)₂—, X is NH and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 82: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—S(═O)₂—, X is NCH₃ and R₃ is H, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 83: Compounds of formula (I) wherein R. is 1-methyl-butyl, Z is—C(═S), X is NCH₃ and R₃ is hydrogen, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 84: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is NCH₃ and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 85: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is S and R₃ is hydrogen, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 86: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S), X is S and R₃ is methyl, and the substituent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 87: Compounds of formula (I) wherein R. is 1-methyl-butyl, Z is—S(═O)₂—, X is NH and R₃ is methyl, and the substituent R₂ for acompound corresponds to any one of lines A.1 to A.183 of Table A.

Table 88: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—S(═O)₂—, X is NCH₃ and R₃ is H, and the substfuent R₂ for a compoundcorresponds to any one of lines A.1 to A.183 of Table A.

Table 89: Compounds of tables 2 to 88, wherein the bond between carbonatoms 22 and 23 is a single bond.

TABLE B Compounds of general formula (I) wherein R₁, R₃ and Z are asdefined in formula (I) and the bond between carbon atoms 22 and 23 is adouble bond. No. R₂ R₄ B.1 —CH₂CH₂CH₂— B.2 —CH₂(CH₂)₂CH₂— B.3—CH₂(CH₂)₃CH₂— B.4 —CH₂CH₂OCH₂CH₂— B.5 —CH₂CH(CH₃)OCH(CH₃)CH₂— B.6—CH₂CH₂SCH₂CH₂— B.7 —CH₂CH₂NHCH₂CH₂— B.8 —CH₂CH₂N(CH₃)CH₂CH₂—

Table 90: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O)—, X is N, R₃ is H, and the substituents R₂and R₄ for a compound correspond to any one of lines B.1 to B.8 of TableB.

Table 91: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═O)—, X is N, R₃ is CH₃, and the substituentsR₂ and R₄ for a compound correspond to any one of lines B.1 to B.8 ofTable B.

Table 92: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S)—, X is N, R₃ is H and the substituents R₂and R₄ for a compound correspond to any one of lines B.1 to B.8 of TableB.

Table 93: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is —C(═S)—, X is N, R₃ is CH₃ and the substituentsR₂ and R₄ for a compound correspond to any one of lines B.1 to B.8 ofTable B.

Table 94: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is SO₂, X is N, R₃ is H and the substituents R₂ andR₄ for a compound correspond to any one of lines B.1 to B.8 of Table B.

Table 95: Compounds of formula (I) wherein R₁ is sec-butyl (B1a) oriso-propyl (B1b), Z is SO₂, X is N, R₃ is CH₃ and the substituents R₂and R₄ for a compound correspond to any one of lines B.1 .to B.8 ofTable B.

Table 96: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O)—, X is N, R₃ is H, and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 97: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═O)—, X is N, R₃ is CH₃, and the substituents R₂ and R₄ for acompound correspond to any one of lines B.1 to B.8 of Table B.

Table 98: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S)—, X is N, R₃ is H and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 99: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is—C(═S)—, X is N, R₃ is CH₃ and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 100: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is SO₂,X is N, R₃ is H and the substituents R₂ and R₄ for a compound correspondto any one of lines B.1 to B.8 of Table B.

Table 101: Compounds of formula (I) wherein R₁ is cyclohexyl, Z is SO₂,X is N, R₃ is CH₃ and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 102: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O)—, X is N, R₃ is H, and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 103: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═O)—, X is N, R₃ is CH₃, and the substituents R₂ and R₄ for acompound correspond to any one of lines B.1 to B.8 of Table B.

Table 104: Compounds of formula (I) wherein R. is 1-methyl-butyl, Z is—C(═S)—, X is N, R₃ is H and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 105: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z is—C(═S)—, X is N, R₃ is CH₃ and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 106: Compounds of formula (I) wherein R₁ is 1-methyl-butyl, Z isSO₂, X is N, R₃ is H and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 107: Compounds of formula (I) wherein R. is 1-methyl-butyl, Z isSO₂, X is N, R₃ is CH₃ and the substituents R₂ and R₄ for a compoundcorrespond to any one of lines B.1 to B.8 of Table B.

Table 108: Compounds of tables 72 to 89, wherein the bond between carbonatoms 22 and 23 is a single bond.

Formulation Examples for use in crop protection (%=percent by weight)

Example F1: Emulsifiable concentrates a) b) c) active ingredient 25% 40%50% calcium dodecylbenzenesulfonate  5%  8%  6% castor oil polyethyleneglycol ether (36 mol EG)  5% — — tributylphenol polyethylene glycolether — 12%  4% (30 mol EO) cyclohexanone — 15% 20% xylene mixture 65%25% 20% Mixing finely ground active ingredient and additives gives anemulsifiable concentrate which yields emulsions of the desiredconcentration on dilution with water. Example F2: Solutions a) b) c) d)active ingredient 80% 10%  5% 95% ethylene glycol monomethyl ether 20% —— polyethylene glycol (mol. wt. 400) — 70% — N-methylpyrrolid-2-one 20%— — — epoxidised coconut oil — — —  1% benzine (boiling range: 160-190□)— — 94% — Mixing finely ground active ingredient and additives gives asolution suitable for use in the form of microdrops. Example F3:Granules a) b) c) d) active ingredient  5% 10%  8% 21% kaolin 94% — 79%54% highly dispersed silicic acid  1% — 13%  7% attapulgite — 90% — 18%The active ingredient is dissolved in dichloromethane, the solution issprayed onto the carrier mixture and the solvent is evaporated off invacuo. Example F4: Wettable powders a) b) c) active ingredient 25% 50%75% sodium lignosulfonate  5%  5% — sodium lauryl sulfate  3% —  5%sodium diisobutylnaphthalenesulfonate —  6% 10% octylphenol polyethyleneglycol ether (7-8 mol —  2% — EO) highly dispersed silicic acid  5% 10%10% kaolin 62% 27% — Active ingredient and additives are mixed togetherand the mixture is ground in a suitable mill, yielding wettable powdersthat can be diluted with water to form suspensions of the desiredconcentration. Example F5: Emulsifiable concentrate active ingredient10% octylphenol polyethylene glycol ether (4-5 mol EO) 3% calciumdodecylbenzenesulfonate 3% castor oil polyethylene glycol ether (36 molEO) 4% cyclohexanone 30% xylene mixture 50% Mixing finely ground activeingredient and additives gives an emulsifiable concentrate which yieldsemulsions of the desired concentration on dilution with water. ExampleF6: Extruder granules active ingredient 10% sodium lignosulfonate 2%carboxymethylcellulose 1% kaolin 87% Active ingredient and additives aremixed together, the mixture is ground, moistened with water, extrudedand granulated and the granules are dried in a stream of air. ExampleF7: Coated granules active ingredient 3% polyethylene glycol (mol. wt.200) 3% kaolin 94% Uniform application of the finely ground activeingredient to the kaolin moistened with poly-ethylene glycol in a mixeryields non-dusty coated granules. Example F8: Suspension concentrateactive ingredient 40% ethylene glycol 10% nonylphenol polyethyleneglycol ether (15 mol EO)  6% sodium lignosulfonate 10%carboxymethylcellulose  1% aqueous formaldehyde solution (37%) 0.2% aqueous silicone oil emulsion (75%) 0.8%  water 32% Mixing finely groundactive ingredient and additives gives a suspension concentrate whichyields suspensions of the desired concentration on dilution with water.

BIOLOGICAL EXAMPLES Example B1 Action Against Spodoptera littoralis

Young soybean plants are sprayed with an aqueous emulsion spray mixturecomprising 12.5 ppm of test compound and, after the spray-coating hasdried, the plants are populated with 10 caterpillars of Spodopteralittoralis in the first stage and then placed in a plastics container. 3days later, the percentage reduction in population and the percentagereduction in feeding damage (% activity) are determined by comparing thenumber of dead caterpillars and the feeding damage on the treated plantswith that on untreated plants.

The compounds of the Tables exhibit good activity in this test. Inparticular, compounds 1.002, 1.004 and 1.005 are more than 90% effectivein this test.

Example B2 Action Against Spodoptera littoralis. Systemic

Maize seedlings are placed in a test solution comprising 12.5 ppm oftest compound. 6 days later, the leaves are cut off, placed on moistfilter paper in a petri dish and infested with 12 to 15 Spodopteralittoralis larvae in the L₁ stage. 4 days later, the percentagereduction in population (% activity) is determined by comparing thenumber of dead caterpillars on the treated plants with that on untreatedplants.

The compounds of the Tables exhibit good activity in this test. Inparticular, compounds 1.001 to 1.008 are more than 90% effective in thistest.

Example B3 Action Against Heliothis virescens

30-35 eggs of Heliothis virescens, from 0 to 24 hours old, are placed onfilter paper in a petri dish on a layer of artificial nutrient. 0.8 mlof the test solution which comprises 12.5 ppm of test compound is thenpipetted onto the filter papers. Evaluation is made 6 days later. Thepercentage reduction in population (% activity) is determined bycomparing the number of dead eggs and larvae on the treated plants withthat on untreated plants. The compounds of the Tables exhibit goodactivity in this test. In particular, compounds 1.002, 1.004 and 1.005are more than 90% effective in this test.

Example B4 Action Against Plutella xylostella Caterpillars

Young cabbage plants are sprayed with an aqueous emulsion spray mixturecomprising 12.5 ppm of test compound. After the spray-coating has dried,the cabbage plants are populated with 10 caterpillars of Plutellaxylostella in the first stage and placed in a plastics container.Evaluation is made 3 days later. The percentage reduction in populationand the percentage reduction in feeding damage (% activity) aredetermined by comparing the number of dead caterpillars and the feedingdamage on the treated plants with that on the untreated plants.

The compounds of Table 1 exhibit good activity against Plutellaxylostella in this test. In particular, compounds 1.002, 1.004 and 1.005are more than 90% effective in this test.

Example B5 Action Against Diabrotica balteata

Maize seedlings are sprayed with an aqueous emulsion spray mixturecomprising 12.5 ppm of test compound and, after the spray-coating hasdried, the maize seedlings are populated with 10 Diabrotica balteatalarvae in the second stage and then placed in a plastics container. 6days later, the percentage reduction in population (% activity) isdetermined by comparing the number of dead larvae on the treated plantswith that on untreated plants. The compounds of the Tables exhibit goodactivity in this test. In particular, compounds 1.002, 1.004 and 1.005are more than 90% effective in this test.

Example B6 Action Against Tetranychus urticae

Young bean plants are populated with a mixed population of Tetranychusurticae and sprayed one day later with an aqueous emulsion spray mixturecomprising 12.5 ppm of test compound. The plants are incubated for 6days at 25° C. and subsequently evaluated. The percentage reduction inpopulation (% activity) is determined by comparing the number of deadeggs, larvae and adults on the treated plants with that on untreatedplants. The compounds of the Tables exhibit good activity in this test.In particular, compounds 1.002, 1.004 and 1.005 are more than 90%effective in this test.

1. A compound of formula

that has the S-configuration at the 4″-position and wherein the bondbetween carbon atoms 22 and 23 is a single or a double bond; R₁ isC₁-C₁₂alkyl, C₃-C₈cycloalkyl; or C₂-C₁₂alkenyl; R₂ is H, C₂-C₁₂alkenyl,C₂-C₁₂alkynyl, —C(═O)—R₅, aryl; wherein the C₂-C₁₂alkenyl,C₂-C₁₂alkynyl, aryl substituents may be unsubstituted or mono-topenta-substituted; R₃ is H, C₂-C₁₂alkenyl or C₂-C₁₂alkynyl; wherein theC₂-C₁₂alkynyl and C₂-C₁₂alkynyl substituents may be unsubstituted ormono-to penta-substituted; X is a bond, O, NR₄ or S; Z is C═O, C═S orSO₂; R₄ is H, C₁-C₈alkyl, C₃-C₈Cycloaklkyl, C₂-C₈alkenyl, C₂-C₈alkynylbenzyl or —C(═O)-R₅; or R₂ and R₄ together are a three-to seven memberedalkylene or alkenylene bridge, wherein the alkylene or elkenylenebridges are unsubstituted or mono to tri-substituted; and wherein one ofthe methylene groups of the three-to seven membered alkylene-oralkenylene-bridge may be replaced by O, NH, S, S(═O) or SO₂; and whereinthe substituents of the mentioned alkyl, alkeny, alkynyl, cycloalkyl,alkylene, alkenylene, aryl radicals as defined under R₂, R₃ and R₄ areselected from the group consisting of OH, ═O, halogen, halo-C₁-C₂alkyl,CN, NO₂, —N₃, C₃-C₈cycloalkyl that is unsubstituted or substituted byfrom one to three methyl groups; norbornylenyl; C₃-C₈cycloalkenyl thatis unsubstituted or substituted by from one to three methyl groups;C₃-C₈halocycloalkyl, C₁-C₁₂alkoxy, C₁-C₆alkoxy-C₁-C₆alkyl,C₃-C₈cycloalkoxy, C₁-C₁₂haloalkoxy, C₁-C₁₂alkythio, C₃-C₈cycloalkylthio,C₁-C₁₂haloalkylthio, C₁-C₁₂alkylsulfinyl, C₃-C₈cycloalkylsulfinyl,C₁-C₁₂haloalkylsulfinyl, C₃-C₈halocycloalkylsulfinyl,C₁-C₁₂alkylsulfonyl, C₃-C₈cycloalkylsulfonyl, C₁-C₁₂haloalkylsulfonyl,C₃-C₈halocycloalkylsulfonyl, C₂-C₈alkenyl, C₂-C₈alkynyl, NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, —C(═O)R₅, —NHC(═O)R₆, ═NO—C₁-C₆alkyl,—P(═O)(OC₁-C₆alkyl)₂; aryl, pyridyl, pyrimidyl, s-triazinyl,1,2,4-triazinyl, thienyl, furyl, tetrahydrofuranyl, pyranyl,tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,triazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl,quinolinyl, quinoxalinyl, benzofuranyl, benzimidazolyl, benzopyrrolyl,benzothiazolyl, indolyl, coumarinyl, indazolyl, aryloxy; and aryl,pyridyl, pyrimidyl, s-triazinyl, 1,2,4-triazinyl, thienyl, furyl,tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl,benzothienyl, quinolinyl, quinoxalinyl, benzofuranyl, benzimidazolyl,benzopyrrolyl, benzothiazolyl, indolyl, coumarinyl, indazolyl, andaryloxy that, depending upon the possibilities of substitution at thering, are mono- to penta-substituted by substituents selected from thegroup consisting of OH, ═O, halogen, CN, NO₂, —N₃, C₁-C₁₂alkyl,C₃-C₈cycloalkyl, C₁-C₁₂haloalkyl, C₁-C₁₂alkoxy, C₁-C₁₂haloalkoxy,C₁-C₁₂alkylthio, C₁-C₁₂haloalkylthio, C₁-C₆alkoxy-C₁-C₆alkyl,dimethylamino-C₁-C₆alkoxy, C₂-C₈alkenyl, C₂-C₈alkynyl, phenoxy andphenyl-C₁-C₆alkyl; phenoxy that is unsubstituted or substituted by fromone to three substituents selected independently of one another fromhalogen, methoxy, trifluoromethyl and trifluoromethoxy;phenyl-C₁-C₆alkoxy that is unsubstituted or substituted in the aromaticring by from one to three substituents selected independently of oneanother from halogen, methoxy, trifluoromethyl and trifluoromethoxy;phenyl-C₂-C₆alkenyl, phenyl-C₂-C₆alkynyl, methylenedioxy,—C(═O)R₅,—O—C(═O)R₈, —NH—C(═O)R₆, NH₂, NH(C₁-C₁₂alkyl), N(C₁C₁₂alkyl)₂,C₁-C₆alkylsulfinyl, C₃-C₈cycloalkylsulfinyl, C₁-C₆haloalkylsulfinyl,C₃-C₈halocycloalkylsulfinyl, C₁-C₆alkylsulfonyl,C₃-C₈cycloalkylsulfonyl, C₁-C₆haloalkylsulfonyl andC₃-C₈halocycloalkylsulfonyl; R₅ is H, OH, SH, NH₂, NH(C₁-C₁₂alkyl),N(C₁-C₁₂alkyl)₂, C₁-C₁₂alkyl, C₃-C₈cycloalkyl, C₁-C₁₂haloalkyl,C₁-C₁₂alkoxy, C₁-C₁₂haloalkoxy, C₁-C₆alkoxy-C₁-C₁₂alkoxy,C₁-C₁₂alkylthio, C₂-C₈alkenyloxy, C₂-C₈alkynyloxy; phenyl, phenoxy,benzyloxy, NH-phenyl, —N(C₁-C₆alkyl)-phenyl, NH—C₁-C₆alkyl-C(═O)—R₇,—N(C₁-C₆alkyl)-C₁-C₆alkyl-C(═O)—R₇; or phenyl, phenoxy, benzyloxy,NH-phenyl or —N(C₁-C₆alkyl)-phenyl each of which is substituted in thearomatic ring by from one to three substituents selected independentlyof one another from halogen, C₁-C₆alkoxy, C₁-C₆haloalkyl andC₁-C₆haloalkoxy; R₆ is H, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl, C₂-C₈alkenyl,C₂-C₆alkynyl, phenyl, benzyl, NH₂, NH(C₁-C₁₂alkyl), N(C₁-C₁₂alkyl)₂,—NH-phenyl or —N(C₁-C₁₂alkyl)-phenyl; and R₇ is H, OH, C₁-C₁₂alkyl,C,-C₁₂alkoxy, C₁-C₆alkoxy-C₁-C₆alkoxy, C₂-C₈alkenyloxy, phenyl, phenoxy,benzyloxy, NH₂, NH(C₁-C₁₂alkyl), N(C₁-C₁₂alkyl)₂, —NH-phenyl or—N(C₁-C₁₂alkyl)-phenyl; or, where applicable, an E/Z isomer, a mixtureof E/Z isomers and/or a tautomer, in each case in free form or in saltform; with the proviso that Z is not C═O when X is a bond, R₂ is H, R₃is hydrogen, the bond between carbon atoms 22 and 23 is a double bondand R₁ is i-propyl or sec-butyl.
 2. A pesticidal composition comprisingas active ingredient at least one compound of formula (I) as describedin claim 1, and at least one adjuvant.
 3. A method of controlling pests,which comprises applying a composition as described in claim 2 to thepests or to the locus thereof.
 4. A process for the preparation of acomposition comprising at least one adjuvant, as described in claim 2,which comprises intimately mixing and/or grinding the active ingredientwith the adjuvant(s).
 5. A method according to claim 3 for protecting aplant propagation material, which comprises treating the propagationmaterial or a planting site of the propagation material.